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Potential new drug target to fight tuberculosis identified
Date:7/30/2008

e sought to do in this research," he says.

One of the study's innovations involved the examination of M. tuberculosis as it interacted with bone marrowderived macrophages during the infective process.

"That's a huge change from standard anti-infective research, which typically deals with the pathogen simply replicating in culture," explains Dr. Vandal. "In our experiments, we wanted to see if biochemical actors would emerge in the infective process that might be inoperative in the usual in vitro setting."

The team specifically focused on changes in the pH (acidity) of the phagosome -- a structure that macrophages use to consume and destroy pathogens, including bacteria.

"As part of this process, the phagosome becomes acidic, which is thought to contribute to its ability to break down and destroy the pathogen," Dr. Ehrt explains. "However, M. tuberculosis appears to survive the acidification process, keeping its own internal pH stable."

How does the bacteria do this, despite being surrounded by the more highly acidic phagosome? To find out, the team used a kind of genetic tweaking that effectively disabled M.tuberculosis' ability to produce a key protein lying at its membrane -- a protease (enzyme) called Rv3671c.

They then watched how the organism fared without it.

"What we observed was pretty amazing -- without functioning Rv3671c, the mutant bacterium was easily destroyed in a low-pH environment, both in culture and inside the more acidic environment of the macrophage," says Dr. Vandal. "This revealed a new point of vulnerability for the bacterium."

The experiment also broke new ground because the researchers were able to accurately gauge the bacterium's internal pH with the organism lying inside a host cell.

"The ability to make those kinds of measurements will expand research into this type of host-pathogen interaction," Dr. Nathan believes.

The next step
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Contact: Andrew Klein
ank2017@med.cornell.edu
212-821-0560
New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College
Source:Eurekalert

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